Abstract:
:Dravet syndrome is a catastrophic, pharmacoresistant epileptic encephalopathy. Disease onset occurs in the first year of life, followed by developmental delay with cognitive and behavioral dysfunction and substantially elevated risk of premature death. The majority of affected individuals harbor a loss-of-function mutation in one allele of SCN1A, which encodes the voltage-gated sodium channel NaV1.1. Brain NaV1.1 is primarily localized to fast-spiking inhibitory interneurons; thus the mechanism of epileptogenesis in Dravet syndrome is hypothesized to be reduced inhibitory neurotransmission leading to brain hyperexcitability. We show that selective activation of NaV1.1 by venom peptide Hm1a restores the function of inhibitory interneurons from Dravet syndrome mice without affecting the firing of excitatory neurons. Intracerebroventricular infusion of Hm1a rescues Dravet syndrome mice from seizures and premature death. This precision medicine approach, which specifically targets the molecular deficit in Dravet syndrome, presents an opportunity for treatment of this intractable epilepsy.
journal_name
Proc Natl Acad Sci U S Aauthors
Richards KL,Milligan CJ,Richardson RJ,Jancovski N,Grunnet M,Jacobson LH,Undheim EAB,Mobli M,Chow CY,Herzig V,Csoti A,Panyi G,Reid CA,King GF,Petrou Sdoi
10.1073/pnas.1804764115subject
Has Abstractpub_date
2018-08-21 00:00:00pages
E8077-E8085issue
34eissn
0027-8424issn
1091-6490pii
1804764115journal_volume
115pub_type
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